Dual Medical Therapy for Treatment of Arrhythmias in Cardiac Sarcoidosis

Anti-arrhythmics can be useful for ventricular arrhythmias in cardiac sarcoidosis (CS) that are refractory to immunosuppression. However, there is conflicting evidence on the efficacy of immunosuppression for treating arrhythmias in CS patients and a lack of data to support using immunosuppression alone as an initial strategy. The objective of this study was to assess for differences in arrhythmia burden over time with currently used immunosuppression and anti-arrhythmic regimens. Patients with CS and implanted cardiac devices were identified from a single-center registry. Study participants were retrospectively classified based on the medication regimen as follows: control (no therapy), immunosuppression, anti-arrhythmics, or dual therapy. Device interrogations were reviewed for premature ventricular contractions (PVCs), non-sustained ventricular tachycardia (NSVT), and device firings over time. Interrogations for 42 patients were reviewed over a mean period of 31 months. Regression analysis showed a significant decrease in the frequencies of PVCs (slope, −1.47; P = .04) and NSVT (slope, −0.05; P = .01) for patients on dual therapy compared to an increase or no change in the other groups. Across all patients, there was no difference between groups in the percentage of patients experiencing device firings. In a subset analysis of patients with implantable cardioverter-defibrillators for primary prevention, 6% on dual therapy required device firings compared to 43% and 40% on single or no therapy, respectively (P = .049, χ2 = 6.02). In conclusion, patients on both immunosuppression and anti-arrhythmics had a reduction in PVCs and NSVT over time. Overall, there were no differences between groups in terms of device firings, except in a subset analysis of patients with no history of ventricular tachycardia.


Introduction
Cardiac sarcoidosis (CS) is associated with a poor prognosis, with patients having an estimated 5-year survival rate of 60% -75%. 1 , 2 It is the cause of 13% -25% of deaths from sarcoidosis in the United States and up to 85% of deaths in Japan. 1 -3 The most common causes of death in this population are progressive heart failure, sustained ventricular arrhythmias, or complete heart block. 2 The rates of sudden cardiac death in CS have been reported as 24% -67% in older studies 4 , 5 ; however, these have likely improved over time with advancements in imaging and treatment. Sustained ventricular arrhythmias are a leading cause of death and have been reported to occur in anywhere from 2% -42% of CS patients. 5 There is currently no standardized approach for the medical management of CS. 6 According to expert consensus, corticosteroids are used to control active infl ammation in most patients. 7 These drugs have been shown to stop the progression of cardiac fi brosis, improve left ventricular ejection fraction, restore the conduction system, and potentially reduce mortality. 1 , 2 , 8 The effectiveness of corticosteroids for treating arrhythmias is unclear. Some studies have found a reduction in rates of ventricular tachycardia (VT) and ventricular fi brillation (VF), while others have shown no improvement or even a possible worsening of the patient ' s condition. 9 -12 As corticosteroid therapy carries signifi cant risks over time, non-steroidal immunosuppression has become increasingly used. 6 , 13 These regimens are typically composed of an antiproliferative or biologic agent with or without low-dose steroids. Methotrexate with low-dose prednisone, for example, has been shown to stabilize cardiac function with fewer side effects than corticosteroids alone. 14 While evidence for these regimens in the setting of arrhythmias is limited, they have shown promise when used long term without interruption. 9 No prior studies have examined the impact of corticosteroid-sparing regimens on arrhythmias in the setting of concurrent anti-arrhythmic therapy.
The current guidelines for the use of anti-arrhythmics in CS are that they can be useful for arrhythmias that are refractory to immunosuppression (class IIa indication). 15 However, data are lacking to support starting with immunosuppression alone, and there is no evidence to guide the selection of an anti-arrhythmic. 15 Previous retrospective studies have reported effective management of ventricular arrhythmias using corticosteroids and anti-arrhythmics together based on 6-month device interrogations and Holter monitors. 16 , 17 One prospective study on CS patients with VT/VF found that 50% experienced arrhythmia recurrence despite corticosteroids and required the addition of an anti-arrhythmic. 11 In this context, our goals were to expand on previous studies and assess the effect of corticosteroid-sparing therapy both with and without anti-arrhythmics. We wanted to compare the effects of various medication regimens, provide information on the real-time impact of medical therapy, and report our experiences from a large sarcoidosis center.

Study population
The study included patients at the University of Cincinnati Sarcoidosis and Interstitial Lung Disease Clinic who had cardiac devices implanted from 2009 -2019. Inclusion criteria were highly probable or probable CS based on the World Association of Sarcoidosis and Other Granulomatous Diseases criteria, 18 an implanted cardiac device, and consistent device interrogations over time. Patients with loop recorders, interrogations at outside hospitals, or non-consistent medication regimens were excluded. Patients with pacemakers were excluded from the analysis of device fi rings (defi ned as anti-tachycardia pacing [ATP] or shock). This study was approved by the University of Cincinnati Medical Center Institutional Review Board and was registered at ClinicalTrials. gov (NCT02356445). Written informed consent was not required. The data collected for this study are available from the corresponding author upon request.

Device indications and interrogation data
The indications for device placement included complete heart block, VT/VF, heart failure with reduced ejection fraction, frequent ectopy with syncope, inducible VT/ VF, and a family history of sudden cardiac death in the setting of CS. Reduced ejection fraction was defi ned as an ejection fraction of ≤ 40%. 19 Sudden cardiac death was defi ned as unexpected death thought to be due to a cardiac arrhythmia. 20 Data from device interrogations were recorded starting at the time of device placement and ending 4 years afterward. All available interrogations in the patients ' charts were reviewed unless there were multiple interrogations in a month, in which case the fi rst interrogation in that month was used. Incorrect arrhythmia classifi cation or inappropriate device therapies were excluded from the results. All device fi ring events defi ned as ATP or shock were independently reviewed by 2 electrophysiologists.

Arrhythmia defi nitions
Premature ventricular contractions (PVCs) were defi ned according to the American College of Cardiology/ American Heart Association (AHA) as " a depolarization of the ventricle which occurs with a coupling interval shorter than that resulting from the intrinsic heart rhythm. " 21 The PVC counts for patients were recorded as PVCs per hour based on the format of most interrogation reports. Non-sustained VT (NSVT) was defi ned as " ≥ 3 consecutive complexes in duration emanating from the ventricles at a rate [of] >100 bpm" and lasting < 30 s. 21 NSVT events were recorded as a monthly average to correct for differences in interrogation frequency. VT was defi ned as " complexes emanating from the ventricles at a rate [of] >100 bpm " lasting for >30 s. 21

Group assignments
The medication treatment protocols at the University of Cincinnati Sarcoidosis Clinic have been described previously by Zhou et al. 6 The patients ' immunosuppression and anti-arrhythmic medication regimens were classifi ed into the following medication groups: no therapy, immunosuppression alone, anti-arrhythmic therapy alone, or dual therapy consisting of both immunosuppressive and anti-arrhythmic drugs. On review, there were various reasons as to why patients were not consistently on any medical therapy, including personal preferences, non-adherence, and/or adverse effects. In order for patients to be classifi ed into a group, they had to have evidence of consistent medication orders and pharmacy dispenses over time. A subgroup analysis of patients on dual therapy who were taking either sotalol

Dual Medical Therapy for Arrhythmias in Cardiac Sarcoidosis
The Journal of Innovations in Cardiac Rhythm Management, November 2022 or amiodarone was performed to evaluate the impact of class III anti-arrhythmics.

Statistical analysis
The data were analyzed using MedCalc version 19.4 (MedCalc Software Ltd., Ostend, Belgium). The normality of distribution for PVC and NSVT data was calculated by the D ' Agostino -Pearson test. The PVC and NSVT data were analyzed using regression, and the significance of the trendline x variable (slope) was calculated to determine the change over time. The median (interquartile range) PVC and NSVT values for each group were compared using the Kruskal -Wallis 1-way analysis of variance test; this analysis can be found in Figures S1 -S4 and Tables S1 -S3 (online). The rates of VT/VF and device therapy were compared between groups using chi-squared tests and reported as P values and χ 2 values. Chi-squared tests were performed in Microsoft Excel for Mac, version 16.37 (Microsoft Corporation, Redmond, WA, USA). P < .05 was considered to be statistically signifi cant.

Baseline characteristics
From the initial registry of 210 patients, 42 were selected based on the study inclusion and exclusion criteria, as can be seen in Figure 2 . The majority of the patients who were excluded did not have accessible device interrogations in their electronic medical record, although several patients had unclear medication regimens or possible alternate diagnoses. Three patients died during the course of the study, including 2 from progressive heart failure and 1 from metastatic cancer.
The baseline characteristics are shown in Table 1 . The mean age at device implantation was 55 years. Twentyfi ve subjects were Black and 17 were White, and 24 were women and 18 were men. The mean follow-up after device placement was 31 months, with a standard deviation of 13 months. The diagnosis of cardiac involvement and indications for the placement of a permanent pacemaker or an implantable cardioverter-defi brillator (ICD) are listed in Table 1 . An example of the most frequently used imaging modality to support the diagnosis of CS can be found in Figures 1 and S1 -S4 and Tables S1 -S3 . There were no signifi cant differences between groups in demographics, cardiac systolic function, coronary artery disease, or indication for device placement.
As can be seen, group 3 had a statistically lower median premature ventricular contractions per hour value than group 4 ( P = .0352). There was no signifi cant difference in the median number of non-sustained ventricular tachycardia events between the 4 groups.

Premature ventricular contraction and nonsustained ventricular tachycardia data
There were 398 interrogations with PVC and NSVT data available for review over a mean follow-up period of 31 (standard deviation, 13) months. Over the course of the study, the median PVC count for patients on antiarrhythmics alone was lower than that for those on dual therapy; otherwise, there were no differences between groups. Patients on dual therapy had a higher starting PVC count than all other groups (median, 60 PVC/h; P < .001). The linear regression model for PVC versus time for the dual therapy group showed a signifi cant decrease   Immunosuppression + Anti-arrhythmic in PVCs over time (slope, − 1.47; R 2 = 0.02; P = .043), as shown in Figure 3 . Patients taking immunosuppression alone had an increase in PVCs over time (slope, 2.64; R 2 = 0.34; P < .001), as seen in Figure 3 . There was an increase in PVCs seen in patients on no therapy and no change for patients on only anti-arrhythmics; graphs for these groups may be found in Figures S1 -S4 .
There were no signifi cant differences in the median number of NSVT events between groups over the course of the study. The dual therapy group had a signifi cant decrease in NSVT over time (slope, − 0.05; R 2 = 0.03; P = .009), as shown in Figure 4 . Patients on no therapy or single therapy did not see a signifi cant change in NSVT frequency over time. A subgroup of patients on immunosuppression plus amiodarone or sotalol had a marked decrease in NSVT events (slope, − 0.13; R 2 = 0.08; P = .038), as seen in Figure 5 .

Ventricular tachycardia/ventricular fi brillation and device fi rings
There were 51 appropriate device therapies for 31 episodes of VT and 20 episodes of VF during the course of the study. Device fi rings (ATP or shock) occurred in 10 of 36 (28%) patients with ICDs, and most of them (n = 10) had multiple arrhythmias/device therapies. Two patients had arrhythmias that were refractory to medical therapy and underwent ablation, including 1 with VT storm. There was no signifi cant difference in the percentage of patients experiencing device fi rings according to the medication regimen, as shown in Table 3 . A subgroup analysis was performed of patients without prior VT/ VF who had ICDs placed for primary prevention. In this subgroup, dual therapy resulted in a signifi cantly lower rate of device fi rings (6%) than single (43%) or no therapy (40%) ( P = .049, χ 2 = 6.02), as can be seen in Table 3 .

Discussion
In this study, the impact of corticosteroid-sparing immunosuppression with and without anti-arrhythmic therapy was assessed in patients with CS. To the best of our knowledge, this is the fi rst report comparing corticosteroid-sparing immunosuppression with anti-arrhythmics to immunosuppression alone for the treatment of arrhythmias in CS. Patients on dual therapy experienced a reduction in PVCs and NSVT events over time, whereas the other treatment groups showed no improvement. Patients on dual therapy did have higher burdens of PVC and NSVT to begin with, which was likely due to selection bias.
Overall, there was a high frequency of device fi rings in the patients studied, and there were no differences across medication groups in rates of device therapy. An Immunosupression + Class III Anti-arrhythmic Figure 5 : Non-sustained ventricular tachycardia (NSVT) episodes per month over time for a subgroup of patients on dual therapy whose regimen included a class III anti-arrhythmic (amiodarone or sotalol). Medical therapy in this group had a significant impact, with almost no NSVT events recorded after 5 months. The P value denotes signifi cance of the x variable (slope).

Dual Medical Therapy for Arrhythmias in Cardiac Sarcoidosis
The Journal of Innovations in Cardiac Rhythm Management, November 2022 interesting fi nding was that a subset of patients who had received ICDs for the primary prevention of sudden cardiac death required fewer device fi rings when on dual medical therapy compared to single or no therapy. This subset analysis may warrant further investigation in future studies but should not detract from the main fi nding of no statistical difference based on the medication regimen.
The current guidelines to treat arrhythmias recommend immunosuppression initially, followed by anti-arrhythmics for refractory arrhythmias. 15 The results of this study suggest that starting with both medication classes could be more effective; however, further research would be needed to determine if this is truly the case. There has been a proposed update that anti-arrhythmics should be considered in CS patients with a history of ventricular arrhythmias even if they are already on immunosuppression. 22 A prospective, randomized study of CS patients with implanted devices tracked in a similar manner could be helpful to conclude if this update would have a positive clinical impact.

Effects of medical therapy on ventricular ectopy
Device interrogations revealed a high degree of variability in the PVC count from patient to patient over the course of the study. This was not unexpected given the variability in PVC frequency in the general population, 23 combined with clinical differences in the study patients. Because of this, PVCs were graphed over time to show the change from baseline with therapy during the follow-up period. Notably, patients on dual therapy experienced a decrease in PVC count over time, while those on immunosuppression alone had increasing PVC counts. The decrease in PVCs could have been clinically significant for patients with very high PVC burdens or those showing symptoms from their PVCs. Several patients in the study had high enough burdens to be at risk for PVCinduced heart failure and therefore would have benefi ted from suppresion. 20 , 24 , 25 However, as PVC treatment does not have a signifi cant effect on outcomes, 20 the need for medical therapy in these patients should not be determined by PVC count and would have to be indicated based on the clinical assessment of cardiac function.
The results showed a reduction in NSVT over time with dual therapy, which was not seen in the other groups. While the negative slope of the NSVT trendline for dual therapy was statistically signifi cant, the magnitude of change was low and not likely to be of clinical importance. Of note, patients on immunosuppression with amiodarone or sotalol had a profound decrease in NSVT, with almost no recurrence after several months of therapy. The class III anti-arrhythmics were likely the main drivers of this, as those on β -blockers and immunosuppression did not see such a decrease. In terms of clinical use, the potential benefi ts of NSVT reduction would need to be balanced with the risk of adverse effects from the anti-arrhythmic medications.

Sustained ventricular arrhythmias and device fi ring
The frequency of VT/VF in our CS patients (28%) was similar to what has been reported previously-that is, 21% over a 4.1-year follow-up period in 1 study and 38% over 2.6 years in another. 9 , 13 Most patients with prior VT/ VF experienced arrhythmia recurrence (71%) despite dual medical therapy. Diffi culty in preventing arrhythmia recurrence in CS patients has been described in prior reports. 13 , 26 Arrhythmias can be diffi cult to control as they are caused by macro -re-entry around scarred myocardium, which is highly arrhythmogenic and not amenable to immunosuppression. 9 , 15 , 27 The recurrence rate of VT in patients on medical therapy in this study (71%) was higher than rates given in previous reports, such as 38% in a study with 37 patients and 57% in another with 21 patients. 16 , 11 All of the patients in our study had ICDs, which may have led to the higher detection rate. Despite the high rate of arrhythmia recurrence in patients with prior VT/VF, there was an improvement in the arrhythmia frequency with treatment over time. Patient 22, for example, had 7 episodes of VF after device implantation, but none after 3 months of methotrexate and amiodarone. Patient 32 had a VT storm with 17 device therapies, underwent ablation, and was maintained on medical therapy without relapse thereafter.
Patients with prior VT/VF were predominantly on dual therapy. The high rates of arrhythmia recurrence in these patients infl uenced the comparison of device fi rings between groups. In patients without prior VT/VF (who had devices placed for primary prevention), there were signifi cantly fewer device fi rings when patients were on dual medical therapy. In these patients, anti-infl ammatories may have reduced lymphocytic infi ltration and scar formation, while anti-arrhythmics would have suppressed rhythms originating from the pre-existing scar.

Limitations and future investigations
There were several limitations to this study due to its retrospective, non-randomized design. Device implantation was not aligned with the initiation of medical therapy in many of the patients; therefore, before-and after-medication arrhythmia counts were not able to be determined. Selection bias was present, in that patients on maximal medical therapy had higher PVC counts to begin with and therefore had greater room for improvement with therapy. There was an uneven distribution of patients in the treatment groups, with fewer patients on no therapy or single-agent therapy compared to dual therapy. The low number of patients in these groups limited the power to detect differences in arrhythmias and device therapy between groups. There was also signifi cant heterogeneity in the specifi c medication regimens patients were taking, which limits the generalizability of these fi ndings to individual patients. Lastly, there was a high-degree variability in PVC and NSVT counts from patient to patient, which made it diffi cult to assess for trends in these data over time and to compare the results between groups. In the future, a prospective, randomized study design with patients assigned to predetermined medication regimens would resolve many of these issues and allow for a more accurate assessment of the impact of medical therapy.

Conclusion
This study was performed to investigate the effectiveness of medical management for arrhythmias in CS patients with implanted devices. We found that patients on dual therapy with both immunosuppression and anti-arrhythmics had a reduction in PVCs and NSVT, while patients on single or no therapy did not. There were no differences between groups in terms of device fi rings across all patients; however, in patients with devices placed for primary prevention, dual therapy led to fewer device fi rings throughout the study. A prospective study with assigned medication regimens and scheduled device interrogations would be ideal to further investigate the optimal medical management of arrhythmias in these patients. Such a study would likely have to be multicentered to have a suffi cient number of patients in each treatment group.